Lee Tae Kyung, Park Cheol, Jeong Soon-Jeong, Jeong Moon-Jin, Kim Gi-Young, Kim Wun-Jae, Choi Yung Hyun
Department of Biology, New York University, New York, NY, 10012, USA.
Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan, 614-714, South Korea.
Drug Dev Res. 2016 Aug;77(5):227-40. doi: 10.1002/ddr.21315. Epub 2016 Jul 1.
Preclinical Research Sanguinarine, an alkaloid isolated from the root of Sanguinaria canadensis and other plants of the Papaveraceae family, selectively induces apoptotic cell death in a variety of human cancer cells, but its mechanism of action requires further elaboration. The present study investigated the pro-apoptotic effects of sanguinarine in human oral squamous cell carcinoma KB cells. Sanguinarine treatment increased DR5/TRAILR2 (death receptor 5/TRAIL receptor 2) expression and enhanced the activation of caspase-8 and cleavage of its substrate, Bid. Sanguinarine also induced the mitochondrial translocation of pro-apoptotic Bax, mitochondrial dysfunction, cytochrome c release to the cytosol, and activation of caspase-9 and -3. However, a pan-caspase inhibitor, z-VAD-fmk, reversed the growth inhibition and apoptosis induced by sanguinarine. Sanguinarine also suppressed the phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt in KB cells, while co-treatment of cells with sanguinarine and a PI3K inhibitor revealed synergistic apoptotic effects. However, pharmacological inhibition of AMP-activated protein kinase and mitogen-activated protein kinases did not reduce or enhance sanguinarine-induced growth inhibition and apoptosis. Collectively, these findings indicate that the pro-apoptotic effects of sanguinarine in KB cells may be regulated by a caspase-dependent cascade via activation of both intrinsic and extrinsic signaling pathways and inactivation of PI3K/Akt signaling. Drug Dev Res 77 : 227-240, 2016. © 2016 Wiley Periodicals, Inc.
临床前研究
血根碱是从加拿大血根草的根以及罂粟科其他植物中分离出的一种生物碱，它能在多种人类癌细胞中选择性地诱导凋亡性细胞死亡，但其作用机制仍需进一步阐明。本研究调查了血根碱对人口腔鳞状细胞癌KB细胞的促凋亡作用。血根碱处理可增加DR5/TRAILR2（死亡受体5/肿瘤坏死因子相关凋亡诱导配体受体2）的表达，并增强半胱天冬酶-8的激活及其底物Bid的裂解。血根碱还诱导促凋亡蛋白Bax向线粒体转位、线粒体功能障碍、细胞色素c释放到细胞质中，并激活半胱天冬酶-9和-3。然而，一种泛半胱天冬酶抑制剂z-VAD-fmk可逆转血根碱诱导的生长抑制和凋亡。血根碱还可抑制KB细胞中磷酸肌醇3-激酶（PI3K）和Akt的磷酸化，而血根碱与PI3K抑制剂共同处理细胞则显示出协同凋亡作用。然而，对AMP激活的蛋白激酶和丝裂原激活的蛋白激酶进行药理抑制并不会降低或增强血根碱诱导的生长抑制和凋亡。总体而言，这些发现表明血根碱在KB细胞中的促凋亡作用可能通过激活内在和外在信号通路以及使PI3K/Akt信号失活，由半胱天冬酶依赖性级联反应来调节。药物研发研究77: 227 - 240, 2016。 © 2016威利期刊公司。
